VaII03lle polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

Background: At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (MC4R) in the development of cancer cachexia. In humans, MC4R mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (VaII03lle, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the VaII03lle polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103lle-allele. Methods: BMI (body mass index in kg/m(2)) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (+/- SD) was 59.0 +/- 14.5 (males: 58.8 +/- 14.0, females 59.2 +/- 14.0). Blood samples were taken for genotyping of the VaII03lle by PCR-RFLP. Results: Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the VaII03lle polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103lle-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103lle-allele carrier status (p > 0.39). Conclusion: Heterozygotes for the 103lle-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, lle103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.